2-29071387-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001029883.3(PCARE):c.2875G>A(p.Ala959Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,613,724 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A959P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 47 hom. )

Consequence

PCARE
NM_001029883.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.679

Publications

4 publications found

Variant links:

Genes affected

PCARE (HGNC:34383): (photoreceptor cilium actin regulator) The protein encoded by this gene is highly expressed in photoreceptors and may associate with the primary cilium of the outer segment. The encoded protein appears to undergo post-translational lipid modification. Nonsense and missense variants of this gene appear to cause a recessive form of retinitis pigmentosa. [provided by RefSeq, Jun 2010]

PCARE Gene-Disease associations (from GenCC):

PCARE-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa 54
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PCARE links:

ENSG00000308575 (HGNC:):

ENSG00000308575 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031301677).

BP6

Variant 2-29071387-C-T is Benign according to our data. Variant chr2-29071387-C-T is described in ClinVar as Benign. ClinVar VariationId is 193141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00173 (263/152318) while in subpopulation SAS AF = 0.0112 (54/4832). AF 95% confidence interval is 0.0088. There are 4 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCARE	NM_001029883.3 link	c.2875G>A	p.Ala959Thr	missense_variant	Exon 1 of 2	ENST00000331664.6	NP_001025054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PCARE	ENST00000331664.6 link	c.2875G>A	p.Ala959Thr	missense_variant	Exon 1 of 2	2	NM_001029883.3	ENSP00000332809.4
ENSG00000308575	ENST00000835145.1 link	n.224+2220C>T		intron_variant	Intron 2 of 2
ENSG00000308575	ENST00000835146.1 link	n.207+2220C>T		intron_variant	Intron 2 of 2
ENSG00000308575	ENST00000835147.1 link	n.171+2220C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00173

AC:

263

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.0354

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00413

AC:

1027

AN:

248692

AF XY:

0.00464

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.0412

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.00810

GnomAD4 exome

AF:

0.00220

AC:

3210

AN:

1461406

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1880

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.00157

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0419

AC:

1094

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0113

AC:

977

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53066

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000607

AC:

675

AN:

1111908

Other (OTH)

AF:

0.00494

AC:

298

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

246

492

739

985

1231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00173

AC:

263

AN:

152318

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41568

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

123

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0112

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68016

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00275

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000250

AC:

ESP6500EA

AF:

0.00299

AC:

ExAC

AF:

0.00365

AC:

442

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 54

Benign:2

Aug 11, 2016

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.0

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0033

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.0

PhyloP100

0.68

PROVEAN

Benign

-0.35

REVEL

Benign

0.032

Sift

Benign

0.21

Sift4G

Uncertain

0.042

Polyphen

0.0

Vest4

0.025

MVP

0.076

MPC

0.013

ClinPred

0.0012

GERP RS

-1.3

Varity_R

0.035

gMVP

0.21

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over